The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Original Article
Oral Nirmatrelvir for High-Risk,
Nonhospitalized Adults with Covid-19
Jennifer Hammond, Ph.D., Heidi Leister‑Tebbe, B.S.N.,
Annie Gardner, M.P.H., M.S.P.T., Paula Abreu, Ph.D., Weihang Bao, Ph.D.,
Wayne Wisemandle, M.A., MaryLynn Baniecki, Ph.D., Victoria M. Hendrick, B.Sc.,
Bharat Damle, Ph.D., Abraham Simón‑Campos, M.D., Rienk Pypstra, M.D.,
and James M. Rusnak, M.D., Ph.D., for the EPIC-HR Investigators*​​
A BS T R AC T
BACKGROUND
Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus
2 main protease (Mpro) inhibitor with potent pan–human-coronavirus activity in vitro.
METHODS
We conducted a phase 2–3 double-blind, randomized, controlled trial in which
symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to
severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive
either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or
death from any cause through day 28, viral load, and safety were evaluated.
RESULTS
A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In
the planned interim analysis of patients treated within 3 days after symptom onset
(modified intention-to treat population, comprising 774 of the 1361 patients in the
full analysis population), the incidence of Covid-19–related hospitalization or death
by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32
percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk
reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir
group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo
group, with 7 deaths. Efficacy was maintained in the final analysis involving the
1379 patients in the modified intention-to-treat population, with a difference of
−5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction,
88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with
nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log10 copies per milliliter when treatment was
initiated within 3 days after the onset of symptoms. The incidence of adverse events
that emerged during the treatment period was similar in the two groups (any adverse
event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse
events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or
placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo.
From Global Product Development, Pfizer, Collegeville, PA (J.H., H.L.-T.); Global
Product Development (A.G.) and Early
Clinical Development (M.L.B.), Pfizer,
Cambridge, MA; Global Product Development, Pfizer, New York (P.A., W.B.,
B.D., R.P.); Global Product Development,
Pfizer, Lake Forest, IL (W.W.); Medical
and Safety, Pfizer, Sandwich, United
Kingdom (V.M.H.); Köhler and Milstein
Research, Mérida, Yucatan, Mexico
(A.S.-C.); and Global Product Development, Pfizer, Tampa, FL (J.M.R.). Dr.
Hammond can be contacted at ­jennifer​
.­hammond@​­pfizer​.­com, or at Pfizer, 500
Arcola Rd., Collegeville, PA 19426.
*A list of the EPIC-HR investigators is provided in the Supplementary Appendix.
This article was published on February 16,
2022, at NEJM.org.
DOI: 10.1056/NEJMoa2118542
Copyright © 2022 Massachusetts Medical Society.
CONCLUSIONS
Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a
risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov
number, NCT04960202.)
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1
The
n e w e ng l a n d j o u r na l
I
nfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
and illness with the associated coronavirus
disease 2019 (Covid-19) continue to threaten
global health.1 Persons with particular characteristics such as older age, current smoking, or
underlying clinical conditions such as cardiovascular disease, diabetes, obesity, and cancer are at
high risk for severe Covid-19 and associated adverse outcomes.2-5 In a meta-analysis, patients with
prespecified coexisting conditions were approximately twice as likely to have progression to
severe Covid-19 and five times as likely to die
from Covid-19 as patients without those conditions.4 Mortality among older adults may be
of
m e dic i n e
greater than that among persons with prespecified coexisting conditions.2,3,6
A need exists for safe and effective oral
Covid-19 treatments that can prevent the progression of infection to more severe disease,
hospitalization, and death; shorten the time to
clinical recovery; and reduce the transmission
rate. Such treatments would help reduce current
strains on health care systems, including overwhelmed hospital facilities and lack of beds in
intensive care units. For nonhospitalized patients
with mild-to-moderate Covid-19, treatment options include monoclonal antibodies, which are
currently available under emergency use authorization by the Food and Drug Administration for
2396 Patients were assessed for eligibility
137 Were excluded
124 Did not meet eligibility criteria
11 Withdrew
2 Had other reason
2246 Underwent randomization
1120 Were assigned to receive nirmatrelvir (300 mg)
and ritonavir (100 mg)
1053 Completed treatment
67 Discontinued treatment
23 Had adverse event
32 Withdrew
3 Were no longer eligible
9 Had other reason
1126 Were assigned to receive placebo
1039 Completed treatment
87 Discontinued treatment
47 Had adverse event
27 Withdrew
1 Had medication error (without
associated adverse event)
1 Was no longer eligible
11 Had other reason
67 Discontinued trial
11 Were lost to follow-up
43 Withdrew
13 Had other reason
77 Discontinued trial
13 Died
9 Were lost to follow-up
43 Withdrew
12 Had other reason
1053 Completed follow-up assessments
1049 Completed follow-up assessments
Figure 1. Randomization, Treatment Assignments, and Follow-up.
Patients were recruited through December 9, 2021, from the United States (105 sites), Bulgaria (30 sites), South Africa (28 sites), Brazil (26 sites), India (19 sites), Mexico (18 sites), Ukraine (17 sites), Turkey (16 sites), Japan and
Spain (10 sites each), Russia (9 sites), Argentina and Colombia (8 sites each), Poland and South Korea (7 sites
each), Hungary (6 sites), Taiwan (5 sites), Malaysia and Czech Republic (4 sites each), and Thailand and Puerto Rico
(3 sites each).
2
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Or al Nirmatrelvir for High-Risk Adults with Covid-19
Table 1. Demographic and Clinical Characteristics of the Patients (Full Analysis Population).*
Nirmatrelvir plus Ritonavir
(N = 1120)
Placebo
(N = 1126)
Total
(N = 2246)
45.00 (18.00–86.00)
46.50 (18.00–88.00)
46.00 (18.00–88.00)
Male
566 (50.5)
582 (51.7)
1148 (51.1)
Female
554 (49.5)
544 (48.3)
1098 (48.9)
800 (71.4)
807 (71.7)
1607 (71.5)
Characteristic
Median age (range) at randomization — yr
Sex — no. of patients (%)
Race or ethnic group — no. of patients (%)†
White
Black
60 (5.4)
50 (4.4)
110 (4.9)
Asian
154 (13.8)
161 (14.3)
315 (14.0)
191 (8.5)
American Indian or Alaska Native
96 (8.6)
95 (8.4)
Multiracial
1 (0.1)
2 (0.2)
3 (0.1)
Not reported
8 (0.7)
9 (0.8)
17 (0.8)
Other or unknown
1 (0.1)
2 (0.2)
3 (0.1)
≤3 days — no. of patients (%)
754 (67.3)
735 (65.3)
1489 (66.3)
>3 days — no. of patients (%)
366 (32.7)
391 (34.7)
757 (33.7)
Time since first symptom
Mean±SD — days
2.93±1.12
2.99±1.09
2.96±1.10
3.00 (0.00–7.00)
3.00 (0.00–9.00)
3.00 (0.00–9.00)
70 (6.2)
70 (6.2)
140 (6.2)
1050 (93.8)
1056 (93.8)
2106 (93.8)
Negative
518 (46.2)
537 (47.7)
1055 (47.0)
Positive
581 (51.9)
568 (50.4)
1149 (51.2)
5.41 (0.00–9.16)
5.30 (0.00–9.15)
5.35 (0.00–9.16)
677 (60.4)
676 (60.0)
1353 (60.2)
Median (range) — days
Covid-19 monoclonal antibody treatment — no. of patients (%)
Received or expected to receive
Not received or did not expect to receive
Serology status — no. of patients (%)
Median viral load (range) — log10 copies per milliliter
Viral load ≥104 copies per milliliter — no. of patients (%)
*Shown are data for all patients who underwent randomization, regardless of whether the drug or placebo was administered.
†Race or ethnic group was reported by the patient.
patients at high risk for progression to severe
Covid-19.7-10 Although monoclonal antibodies significantly reduce the risk of progression to severe Covid-19,11-13 limitations to their use include
the need for administration and monitoring in a
health care setting and the potential for reduced
efficacy against emerging SARS-CoV-2 variants.10
Nirmatrelvir (PF-07321332) is an orally administered antiviral agent targeting the SARSCoV-2 3-chymotrypsin–like cysteine protease enzyme (Mpro).14 Mpro is an attractive antiviral target
because it is essential in the viral replication
cycle (i.e., in processing viral polyproteins into
functional units)15 and has a low likelihood of
off-target activity, owing to the absence of rec-
ognized human analogues.16 Nirmatrelvir exhibited potent inhibition of Mpro activity and virus
replication across a wide spectrum of coronaviruses in vitro; oral administration was associated with SARS-CoV-2 lung titers that were significantly lower than titers associated with
placebo in a mouse model.14 Nirmatrelvir is metabolized mainly by CYP3A4.14 Coadministration
of nirmatrelvir with a low dose (100 mg) of
ritonavir, a CYP3A4 inhibitor, enhances nirmatrelvir pharmacokinetics.14,17 A first-in-human
study in healthy participants (ClinicalTrials.gov
number, NCT04756531) showed a clinically acceptable safety profile up to the highest dose
and exposure evaluated (500 mg of nirmatrelvir
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3
The
n e w e ng l a n d j o u r na l
plus 100 mg of ritonavir twice daily for 10 days).
Simulations showed that twice-daily administration of 300 mg of nirmatrelvir plus 100 mg of
ritonavir achieves and maintains plasma trough
concentrations approximately five to six times
the in vitro 90% effective concentration of nirmatrelvir (i.e., the concentration at which 90%
inhibition of SARS-CoV-2 viral replication is observed) (data on file).
The EPIC-HR trial (Evaluation of Protease
Inhibition for Covid-19 in High-Risk Patients)
evaluated the safety and efficacy of nirmatrelvir
plus ritonavir in nonhospitalized adults with mildto-moderate Covid-19 at high risk for progression to severe disease.
Me thods
of
m e dic i n e
protocol, which is available at NEJM.org and
includes the statistical analysis plan.
Procedures
Eligible patients were randomly assigned in a
1:1 ratio, by means of an interactive response
technology system, to receive either nirmatrelvir plus ritonavir or matched placebo every 12
hours for 5 days (10 doses total). Randomization was stratified by geographic region and by
receipt or expected receipt (based on investigator opinion) of Covid-19 monoclonal antibodies. Nirmatrelvir and matching placebo were
manufactured by Pfizer, ritonavir tablets were
manufactured and tested by Hetero Labs, and
blinding of the tablets was performed by Pfizer
through over-encapsulation. The assessment
schedule is outlined in Figure S1.
Objectives, Patients, and Oversight
This phase 2–3, double-blind, randomized, placebo-controlled trial evaluated the efficacy, viral
load, and safety associated with the use of nirmatrelvir plus ritonavir among nonhospitalized,
symptomatic adults with Covid-19 who were at
high risk for progression to severe disease. Eligible patients were required to be at least 18 years
old; to have confirmed SARS-CoV-2 infection
and symptom onset no more than 5 days before
randomization, with at least one sign or symptom of Covid-19 on the day of randomization
(see Table S1 in the Supplementary Appendix,
available with the full text of this article at
NEJM.org); and to have at least one characteristic or coexisting condition associated with high
risk of progression to severe Covid-19.2-4,6 The
trial was approved by an ethics committee at
each site, and all participants provided written
informed consent.
Key exclusion criteria were previous confirmed SARS-CoV-2 infection or hospitalization
for Covid-19, anticipated need for hospitalization
within 48 hours after randomization, and prior
receipt of convalescent Covid-19 plasma or
SARS-CoV-2 vaccine. The Supplementary Appendix provides additional inclusion and exclusion
criteria and information on prohibited prior or
concomitant therapies, trial blinding, ethical
conduct, and responsibilities of the sponsor. All
the data were available to all the authors, who
vouch for the accuracy and completeness of the
data as well as the adherence of the trial to the
4
Efficacy
The primary objective of the trial was to assess
the efficacy of nirmatrelvir plus ritonavir as
compared with placebo by comparing the percentage of patients with Covid-19–related hospitalization or death from any cause through day
28 in the two groups. This comparison was performed in the modified intention-to-treat population, which included patients whose treatment
began within 3 days after the onset of Covid-19
signs and symptoms and excluded patients who
at randomization had received or were expected
to receive monoclonal antibody treatment (see
Table S2 for definitions of all analysis populations). A key secondary end point was the primary comparison analyzed similarly among patients whose treatment began within 5 days after
the onset of Covid-19 signs and symptoms. A
supplementary analysis was conducted to include patients who had received or were expected to receive monoclonal antibody treatment.
Prespecified subgroup analyses of primary and
secondary end points were conducted, and nominal 95% confidence intervals were provided to
evaluate whether the treatment effect varied according to age, sex, race, body-mass index (BMI,
the weight in kilograms divided by the square of
the height in meters), baseline serology status
and viral load, and number of baseline coexisting conditions and risk factors (see the Supplementary Appendix for details on the serology
methods).
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Or al Nirmatrelvir for High-Risk Adults with Covid-19
Viral Load
Detection and quantification of SARS-CoV-2 viral
load in nasopharyngeal swabs by reverse-transcriptase–polymerase-chain-reaction assay was a
secondary end point. Nasopharyngeal or nasal
swabs were collected on day 1 (baseline) and
days 3, 5, 10, and 14.
Safety
Safety end points included adverse events that
emerged during or after the treatment period
(starting on or before day 34), serious adverse
events, and adverse events leading to discontinuation of the trial drug or placebo, as coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 24.0. Incidence data
were provided for each treatment group within
the safety analysis population, which included
all patients who received at least one dose of
drug or placebo. Investigators actively collected
safety information through day 34.
virus at baseline were excluded from the analysis. Viral loads below the limit of detection (2 log10
copies per milliliter) were imputed as 1.70 log10
copies per milliliter.
On the basis of a group sequential design
utilizing a Lan–DeMets alpha-spending function
with an O’Brien–Fleming stopping boundary,18,19
a prespecified interim analysis of the primary
end point for efficacy, futility, and sample size
re-estimation was performed by an external data
monitoring committee once approximately 45%
of patients in the primary analysis population
had completed assessments through day 28. The
prespecified significance level for early termination was 0.002 for efficacy and 0.9184 for futility. See the Supplementary Appendix for additional details regarding the statistical analyses,
including handling of missing data.
R e sult s
Patients
Statistical Analysis
The trial planned to enroll approximately 3000
patients. Of these, 1717 were to be included in
the primary analysis to ensure 90% power, accounting for an interim analysis, to detect a 50%
difference in Covid-19–related hospitalization or
death from any cause with nirmatrelvir plus
ritonavir, as compared with placebo (anticipated
event rate with placebo, 7.0%)11 in patients who
had undergone randomization within 3 days
after symptom onset and who received no monoclonal antibodies.
The primary analysis compared proportions
of patients in the two groups who were hospitalized for Covid-19 or died from any cause through
day 28, using the Kaplan–Meier method to account for all patients, including those prematurely withdrawn from the trial or lost to followup. A z-test was used for the comparison, with
standard errors estimated from Greenwood’s
formula. The end points were tested sequentially
(i.e., first the primary end point, then the first
key secondary end point, and finally other secondary end points) to ensure the overall alpha
level of 0.05.
Changes from baseline to day 5 in log10transformed viral load were compared between
treatment groups with an analysis of covariance
(ANCOVA) model adjusted for baseline viral load
and serology status. Patients without detectable
Between July 16 and December 9, 2021, a total of
2246 patients were enrolled at 343 sites worldwide; 1120 received nirmatrelvir plus ritonavir
and 1126 received placebo (Fig. 1). Of the 2246
patients, 2102 completed safety follow-up (day 34);
no patients had completed long-term follow-up at
the time of this analysis (i.e., through week 24).
Patient characteristics were similar in the two
groups (Table 1) and were largely representative
of the expected patient population (Table S3).
The median age was 46 years; 1148 patients
(51.1%) were male, and 1607 (71.5%) and 315
(14.0%) were White and Asian, respectively. The
most common prespecified characteristics and
coexisting conditions associated with a risk of
progression to severe Covid-19 at baseline were
a BMI of 25 or above (1807 patients [80.5%]),
current smoking (876 [39.0%]), and hypertension (739 [32.9%]); 1370 patients (61.0%) had
two or more such characteristics or coexisting
conditions. Most patients (2106 [93.8%]) had not
received or were not expected to receive monoclonal antibodies for Covid-19 treatment at randomization, and 1489 (66.3%) received the first
dose of the trial drug or placebo within 3 days
after the onset of symptoms. Before receiving
the trial drug or placebo, 4 patients had received
monoclonal antibodies for Covid-19 treatment
(3 in the nirmatrelvir group and 1 in the placebo
group).
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5
The
n e w e ng l a n d j o u r na l
m e dic i n e
of
A Outcomes According to Time Since Onset of Covid-19 Symptoms
Treated ≤3 Days after Onset of Symptoms
(modified intention-to-treat population)
Treated ≤5 Days after Onset of Symptoms
Nirmatrelvir+ritonavir
(N=697)
Placebo
(N=682)
Nirmatrelvir+ritonavir
(N=1039)
Placebo
(N=1046)
5 (0.72)
5 (0.72)
0
27.29
27.45
0.72 (0.30 to 1.73)
–5.81±1.01
−7.78 to −3.84
<0.001
44 (6.45)
44 (6.45)
9 (1.32)
26.19
27.25
6.53 (4.90 to 8.68)
8 (0.77)
8 (0.77)
0
27.05
27.20
0.78 (0.39 to 1.56)
−5.62±0.81
−7.21 to −4.03
<0.001
66 (6.31)
65 (6.21)
12 (1.15)
25.97
27.05
6.40 (5.06 to 8.08)
Patients with event — no. (%)
Hospitalization for Covid-19
Death from any cause
Average time at risk for event — days
Average follow-up — days
Estimated percentage with event (95% CI) — %
Difference (±SE) from placebo — percentage points
95% CI of difference
P value
B Covid-19–Related Hospitalization or Death from Any Cause through Day 28 among Patients Treated ≤5 Days after Symptom Onset
100
10
9
8
7
6
5
4
3
2
1
0
Cumulative Incidence (%)
90
80
70
60
50
40
30
20
Nirmatrelvir+ritonavir (N=1039; 8 events)
Placebo (N=1046; 66 events)
Placebo
Nirmatrelvir+ritonavir vs. placebo: Difference, −5.62% (95% CI, −7.21 to −4.03)
P<0.001
Nirmatrelvir+ritonavir
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
10
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
997
955
995
953
993
951
993
948
993
948
993
948
992
945
Days
No. at Risk
NMV-r
Placebo
1039
1046
1034
1042
1023
1015
1013
990
1007
977
1004
963
1002
959
1000
959
C Subgroup Analysis
Subgroup
Nirmatrelvir+Ritonavir
Placebo
Difference from Placebo (95% CI)
no. of events/total no.
Overall
Time since symptom onset
≤3 days
>3 days
Age
<65 yr
≥65 yr
Sex
Male
Female
Body-mass index
<25
25 to <30
≥30
Diabetes mellitus
Yes
No
Baseline SARS-CoV-2 serology status
Negative
Positive
Received or expected to receive Covid-19
monoclonal antibody treatment
Yes
No
percentage points
8/1039
66/1046
−5.62 (−7.21 to −4.03)
5/697
3/342
44/682
22/364
−5.81 (−7.78 to −3.84)
−5.23 (−7.91 to −2.55)
7/908
1/131
46/909
20/137
−4.35 (−5.91 to −2.79)
−13.93 (−20.07 to −7.80)
4/520
4/519
41/540
25/506
−6.93 (−9.32 to −4.53)
−4.23 (−6.29 to −2.17)
1/209
3/458
4/371
9/207
28/466
29/373
−3.88 (−6.83 to −0.94)
−5.44 (−7.75 to −3.13)
−6.85 (−9.82 to −3.87)
2/125
6/913
9/127
57/919
−5.51 (−10.51 to −0.52)
−5.63 (−7.30 to −3.96)
7/487
1/540
58/505
8/528
−10.25 (−13.28 to −7.21)
−1.34 (−2.45 to −0.23)
1/70
8/1039
2/69
66/1046
−1.51 (−6.40 to 3.37)
−5.62 (−7.21 to −4.03)
−24
6
−20
−16
−12
−8
−4
0
4
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Or al Nirmatrelvir for High-Risk Adults with Covid-19
to –3.84; P<0.001) and an 88.9% relative risk
reduction in Covid-19–related hospitalization or
death from any cause. Nine deaths were reported
in the placebo group and none in the nirmatrelvir
group.
After results of the primary analysis were
found to be significant, the first key secondary
analysis was performed among patients who
commenced treatment within 5 days after symptom onset to evaluate hospitalization for Covid-19
or death from any cause. In the final analysis of
this population, 8 of 1039 patients (0.77%) in the
nirmatrelvir group and 66 of 1046 (6.31%) in the
placebo group were hospitalized for Covid-19 or
died from any cause through day 28 (P<0.001),
corresponding to an 87.8% relative risk reduction (Fig. 2A and 2B).
When 139 patients who received or were expected to receive monoclonal antibody treatment
were included in the evaluation (6.25% of the
total analysis population), hospitalizations due
to Covid-19 or deaths from any cause were 0.81%
and 6.10% in the nirmatrelvir and placebo groups,
respectively (Table S4). Results from subgroup
analyses were consistent, regardless of age, sex,
Efficacy
race, BMI, baseline serology status, viral load,
In the planned interim analysis of patients treated coexisting conditions, or number of coexisting
within 3 days after symptom onset (modified in- conditions at baseline (Fig. 2C and Fig. S2A
tention-to treat population, comprising 774 of the through C).
1361 patients in the full analysis population),
significantly fewer recipients of nirmatrelvir Viral Load
plus ritonavir had Covid-19–related hospitaliza- Data on SARS-CoV-2 viral load collected at basetion or death by day 28 (3 of 389 patients line and day 5 were evaluated in 1574 patients
[0.77%]; 0 deaths) than placebo recipients (27 of (i.e., in 70% of the 2246 patients). After adjust385 [7.01%]; 7 deaths), a difference of −6.32 ment for baseline viral load, serology status, and
percentage points (95% CI, –9.04 to –3.59; geographic region, nirmatrelvir plus ritonavir
P<0.001). The relative risk reduction was 89.1%. reduced viral load at day 5 by an adjusted mean
In the final analysis of patients who com- (±SE) of an additional 0.868±0.105 log10 copies
menced treatment within 3 days after symptom per milliliter (95% CI, –1.074 to –0.6615; P<0.001)
onset and did not receive monoclonal antibodies when treatment was initiated within 3 days after
(modified intention-to-treat population, compris- symptom onset, a decrease in viral load by a facing 1379 of the 2246 patients in the full analysis tor of 10 relative to placebo, and 0.695±0.085
population), 5 of 697 patients (0.72%) in the nir- log10 copies per milliliter (95% CI, –0.861 to
matrelvir group and 44 of 682 (6.45%) in the –0.530; P<0.001) when treatment was initiated
placebo group were hospitalized for Covid-19 or within 5 days after symptom onset (Fig. 3A and
died from any cause through day 28 (Fig. 2A). Fig. S3A). When patients who received or were
With use of the Kaplan–Meier method, the esti- expected to receive monoclonal antibodies for
mated event rates of Covid-19–related hospital- Covid-19 treatment were included in the analyization or death from any cause at 28 days were sis, nirmatrelvir plus ritonavir showed a similar
0.72% and 6.53% in the nirmatrelvir and placebo antiviral effect (nirmatrelvir plus ritonavir regroups, respectively, corresponding to a differ- duced viral load at day 5 by an additional
ence of −5.81 percentage points (95% CI, –7.78 0.689±0.082 log10 copies per milliliter; 95% CI,
Figure 2 (facing page). Efficacy of Nirmatrelvir plus
Ritonavir (NMV-r) in Preventing Covid-19–Related Hospitalization or Death from Any Cause through Day 28.
Panel A shows efficacy results among patients who
were treated within 3 days and within 5 days after
symptom onset and who did not receive or were not expected to receive Covid-19 therapeutic monoclonal antibodies at randomization. The average time at risk for
an event was computed as the time to the first event or
as the time to the last day of participation or day 28,
whichever was earlier. The average study follow-up was
computed as the time to the last day of participation or
day 28, whichever was earlier. Panel B shows the cumulative percentage of patients with Covid-19–related hospitalization or death from any cause through day 28
among patients treated within 5 days after symptom
onset. The cumulative percentage was estimated for
each treatment group with use of the Kaplan–Meier
method. The inset shows the same data on an expanded y axis. Panel C shows subgroup analysis of the differences of the proportions of patients treated within 5
days after symptom onset who had Covid-19–related
hospitalization or death from any cause through day
28, estimated for each treatment group with use of the
Kaplan–Meier method. P values are based on normal
approximation of the data. Study populations are described in Table S2.
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7
The
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Nirmatrelvir+ritonavir (NMV-r)
of
m e dic i n e
Placebo
A Overall Population
Mean Change from
Baseline
0
−2
−4
−6
−8
Base- 1
line
2
3
4
5
6
7
8
9 10 11 12 13 14
Days
No. at Risk
NMV-r
Placebo
552
553
Mean (±SE) Change from
Baseline vs. Placebo
P Value
529
508
525
507
–0.55 –0.8
±0.11 ±0.10
<0.001 <0.001
B Seronegative
502
475
–0.44
±0.10
<0.001
C Seropositive
0
Mean Change from
Baseline
Mean Change from
Baseline
0
−2
−4
−6
−8
Base- 1
line
2
3
4
5
6
7
8
296
267
−0.67
±0.14
293
273
−0.21
±0.12
<0.001 <0.001
<0.001
0.07
NMV-r
Placebo
2
3
4
5
6
7
8
9 10 11 12 13 14
Days
203
200
−0.11
±0.12
211
219
−0.06
±0.11
0.001
0.37
0.60
0.01
Mean Change from
Baseline
0
−4
−6
Base- 1
line
222
208
223
215
−0.58 −0.44
±0.18 ±0.16
E Baseline Viral Load >107 copies/ml
−2
−8
231
233
Mean (±SE) Change
from Baseline
vs. Placebo
P Value
0
Mean Change from
Baseline
−6
No. at Risk
304
297
294
284
−0.56 −1.20
±0.14 ±0.13
D Baseline Viral Load >104 copies/ml
2
3
4
5
6
7
8
−2
−4
−6
−8
Base- 1
line
9 10 11 12 13 14
Days
No. at Risk
2
3
4
5
6
7
8
9 10 11 12 13 14
Days
No. at Risk
443
442
Mean (±SE) Change
from Baseline
vs. Placebo
P Value
8
−4
Base- 1
line
Days
318
312
Mean (±SE) Change
from Baseline
vs. Placebo
P Value
NMV-r
Placebo
−2
−8
9 10 11 12 13 14
No. at Risk
NMV-r
Placebo
507
500
−0.16
±0.08
<0.045
424
408
419
402
−0.66 −1.00
±0.12 ±0.12
408
379
−0.43
±0.12
408
396
−0.15
±0.10
<0.001 <0.001
<0.001
0.13
NMV-r
Placebo
224
202
Mean (±SE) Change
from Baseline
vs. Placebo
P Value
213
209
191
185
−0.88 −1.39
±0.16 ±0.15
204
171
−0.73
±0.17
208
176
−0.16
±0.14
<0.001 <0.001
<0.001
0.25
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Or al Nirmatrelvir for High-Risk Adults with Covid-19
Figure 3 (facing page). Change from Baseline in Log10 Transformed Viral Load over Time (Modified Intentionto-Treat Population).
Panel A shows the adjusted mean change in viral load
from baseline among all the patients who received at
least one dose of the drug or placebo, had at least one
visit between day 1 and day 28, did not receive or were
not expected at baseline to receive Covid-19 therapeutic
monoclonal antibody treatment, and were treated within 3 days after the onset of Covid-19 (modified intention-to-treat population). Panel B shows findings for
the subgroup of patients whose baseline SARS-CoV-2
serology status was negative, and Panel C shows findings for the subgroup of patients whose baseline SARSCoV-2 serology status was positive. Panel D shows
findings among patients whose baseline viral load was
more than 10 4 copies per milliliter, and Panel E shows
findings among patients whose baseline viral load was
more than 107 copies per milliliter. Patients were excluded from the analysis if the viral load was not detected or if data on baseline viral load were missing.
Results obtained with unvalidated swabs were also excluded. Results were obtained with the use of a mixedeffects repeated-measures analysis of covariance model. Treatment, visit, and visit-by-treatment interactions
were fixed effects in the analysis. Geographic region,
baseline SARS-CoV-2 serology status, baseline viral
load, and nasopharyngeal sample site were covariates,
and participant was a random effect.
–0.849 to –0.529 relative to placebo) (Fig. S4).
Results from subgroup analyses were consistent
with those in the overall population regardless
of baseline viral load and serology status (Fig. 3B
through E and Fig. S3B through E). Preliminary
analysis of 731 matched samples from day 1 and
day 5 with available sequencing data suggests no
significant associations between Mpro mutations
and treatment failure.
Safety
The incidence of adverse events that emerged
during or after the treatment period was similar
among recipients of nirmatrelvir plus ritonavir
(22.6%) and recipients of placebo (23.9%) (Table 2). The most frequently reported such events
(affecting at least 1% of patients) — both events
considered by the investigator to be related to
the assigned drug or placebo and those not considered to be related — among recipients of
nirmatrelvir plus ritonavir were dysgeusia (5.6%,
as compared with 0.3% of placebo recipients),
diarrhea (3.1% vs. 1.6%), fibrin D-dimer increase
(1.9% vs. 2.8%), alanine aminotransferase increase (1.5% vs. 2.4%), headache (1.4% vs. 1.3%),
creatinine renal clearance decrease (1.4% vs. 1.6%),
nausea (1.4% vs. 1.7%), and vomiting (1.1% vs.
0.8%); these adverse events were nonserious, were
mostly grade 1 or 2, and resolved (Table S5).
Adverse events considered by the site investigator to be related to the trial drug or placebo
were more common among recipients of nirmatrelvir plus ritonavir (7.8%) than among placebo
recipients (3.8%). This difference was largely
attributed to dysgeusia (4.5% vs. 0.2%) and diarrhea (1.3% vs. 0.2%), which were the only treatment-related adverse events reported in at least
1% of recipients of nirmatrelvir plus ritonavir;
the majority of such events were resolved and
were grade 1 or 2, with the exception of one case
of grade 3 dysgeusia. Percentages were lower
and similar across groups for related grade 3
events (nirmatrelvir plus ritonavir, 0.5%; placebo, 0.4%) and grade 4 events (nirmatrelvir plus
ritonavir, 0; placebo, <0.1%).
Patients who received nirmatrelvir plus ritonavir reported fewer grade 3 or 4 adverse events
than placebo recipients (4.1% vs. 8.3%), fewer
serious adverse events (1.6% vs. 6.6%), and fewer
adverse events leading to discontinuation of the
drug or placebo (2.1% vs. 4.2%) (Table 2). The
most frequently reported serious adverse events
(those occurring in at least 2 patients) among
recipients of nirmatrelvir plus ritonavir were
Covid-19 pneumonia (6 patients [0.5%], as compared with 37 [3.3%] in the placebo group),
Covid-19 (2 patients [0.2%], as compared with 8
[0.7%]), and decreased renal creatinine clearance
(2 patients [0.2%], as compared with 3 [0.3%]);
none were considered by the investigator to be
related to nirmatrelvir or placebo (Table S6).
Through day 34, no serious adverse events resulted in death among recipients of nirmatrelvir
plus ritonavir; there were 13 deaths among placebo recipients, and all the deaths were Covid-19–related (Covid-19 pneumonia, 8 patients;
Covid-19, 3 patients; pneumonitis, 1 patient; and
acute respiratory failure, 1 patient). Adverse events
that led to discontinuation of the trial drug or
placebo in more than one patient in either treatment group (listed in order of frequency across
treatment groups) were Covid-19 pneumonia,
nausea, decreased renal creatinine clearance,
vomiting, Covid-19, decreased glomerular filtration rate, pneumonia, pneumonitis, decreased
white-cell count, and dysgeusia. Among recipients of nirmatrelvir plus ritonavir who discon-
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9
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n e w e ng l a n d j o u r na l
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m e dic i n e
Table 2. Summary of Adverse Events, Serious Adverse Events, and Adverse Events Leading to Discontinuation through
Day 34 (Safety Analysis Population).*
Adverse Event Category
Nirmatrelvir plus
Ritonavir
(N = 1109)
Placebo
(N = 1115)
476
525
Events that emerged during treatment period
No. of adverse events
Patients with adverse events — no. (%)
251 (22.6)
266 (23.9)
Serious adverse event
Any adverse event
18 (1.6)
74 (6.6)
Maximum grade 3 or 4 adverse event
45 (4.1)
93 (8.3)
0
13† (1.2)
Discontinued drug or placebo because of adverse event
23 (2.1)
47 (4.2)
Had dose reduction or temporary discontinuation owing to
adverse event
4 (0.4)
4 (0.4)
123
52
Any adverse event
86 (7.8)
42 (3.8)
Serious adverse event
1 (<0.1)
0
Maximum grade 3 or 4 adverse event
5 (0.5)
5 (0.4)
Maximum grade 5 adverse event
Events considered to be related to drug or placebo
No. of adverse events
Patients with adverse events — no. (%)
Maximum grade 5 adverse event
0
0
Discontinued drug or placebo because of adverse event
9 (0.8)
7 (0.6)
Had dose reduction or temporary discontinuation owing to
adverse event
2 (0.2)
3 (0.3)
*Shown are data for all patients who received at least one dose of drug or placebo.
†All reported deaths were related to Covid-19; causes of death included Covid-19 pneumonia (8 patients), Covid-19 (3
patients), pneumonitis (1 patient), and acute respiratory failure (1 patient).
tinued the drug owing to an adverse event,
events were mostly mild-to-moderate (grade 1 or 2)
and were resolved or resolving at the time of this
analysis. Twelve patients had an adverse event
that was life-threatening (grade 4) (2 recipients
of nirmatrelvir plus ritonavir and 10 placebo recipients). Few events (≤0.8%) leading to discontinuation of drug or placebo in either treatment
group were considered by the investigator to be
related to the trial drug or placebo.
Discussion
Results from this phase 2–3 trial in unvaccinated persons demonstrate the efficacy of oral administration of nirmatrelvir (300 mg) with ritonavir (100 mg) every 12 hours for 5 days. This
regimen, commencing within 3 days after the
onset of Covid-19 symptoms, was found to be
efficacious at the planned interim analysis, with
10
an 89.1% relative risk reduction in Covid-19–related
hospitalization or death from any cause by day
28 among nonhospitalized adults at high risk
for progression to severe disease. At the full
analysis, relative risk reductions of 88.9% and
87.8% were observed among patients commencing treatment within 3 days and within 5 days
after symptom onset, respectively, with 0 deaths
occurring in the group that received nirmatrelvir
plus ritonavir and 13 deaths occurring in the
placebo group. This efficacy was supported by
subgroup analyses of the primary end point;
patients treated with nirmatrelvir plus ritonavir
either had no Covid-19–related hospitalization
or death from any cause or had a risk that was
significantly lower than that with placebo, regardless of age, sex, race, BMI, baseline serology
status, viral load, coexisting conditions, or number of coexisting conditions at baseline. Treatment with nirmatrelvir plus ritonavir was also
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Or al Nirmatrelvir for High-Risk Adults with Covid-19
associated with an additional reduction in SARSCoV-2 viral load at day 5, by a factor of 10, as
compared with placebo.
Nirmatrelvir plus ritonavir targets an essential
protein that is conserved across coronaviruses.15,20,21
Given the well-conserved nature of the Mpro active site, inhibitors of Mpro may be more likely to
retain activity against future variants.20,21
Fewer serious adverse events and adverse
events leading to treatment discontinuation occurred with nirmatrelvir plus ritonavir than with
placebo. The most frequent adverse events occurring more often in recipients of nirmatrelvir
plus ritonavir were dysgeusia, diarrhea, and
vomiting.
The concomitant use of nirmatrelvir plus
ritonavir and certain drugs may result in potentially important drug interactions. Such interactions need to be managed through dose reduction of the concomitant medication, use of an
alternative concomitant medication, increased
monitoring for adverse events or concomitant
medication drug levels, temporary discontinuation
of concomitant medications, or avoidance of coadministration. Drug interactions with low-dose
ritonavir (100 mg) given over a short duration of
5 days for treatment of Covid-19 are likely to be
of lesser clinical consequence than long-term
use of low-dose or standard-dose (600 mg) ritonavir for patients with human immunodeficiency virus. Nirmatrelvir plus ritonavir is contraindicated with use of certain drugs because of the
risk of serious adverse events.
The trial has several strengths and limitations.
Patients from diverse regions were included, enabling broad geographic generalizability. Although
only persons at high risk for progression to severe Covid-19 were included, the corresponding
demographic and clinical characteristics are relatively common: cardiovascular disease, obesity,
and diabetes have been estimated at 7 to 14.9%
worldwide prevalence in recent years,22-24 and approximately 12% of the world population in
2017 was 60 years of age or older.25 Of importance, this trial was restricted to unvaccinated
persons, although a separate, ongoing trial of
nirmatrelvir plus ritonavir (EPIC-Standard Risk
[SR]; NCT05011513) includes vaccinated, highrisk persons.
Molnupiravir is an orally administered antiviral Covid-19 treatment that currently has emergency use authorization in the United States for
use in the high-risk, nonhospitalized population,26 achieving a 30% reduction in Covid-19–
related hospitalization or death through 29 days
after randomization.27,28 Covid-19 therapeutic
monoclonal antibodies are associated with relative risk reductions of approximately 70 to 85%
against mild-to-moderate Covid-19 in outpatient
settings11-13; however, monoclonal antibodies require intravenous or subcutaneous administration in a health care setting, and they may be
less effective against emerging variants harboring mutations in the monoclonal antibody–targeted SARS-CoV-2 spike protein.7-9,29,30 Remdesivir, an agent administered intravenously that is
approved for use in patients hospitalized for
Covid-19, has shown an 87% reduction in the
risk of progression to severe disease in the outpatient setting.31
Our data show that treatment with nirmatrelvir plus ritonavir early in Covid-19 illness can
decrease progression to severe disease and
quickly reduce SARS-CoV-2 viral load.
Supported by Pfizer.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank all the patients who volunteered for this trial,
the study site personnel for their contributions, and the members of the C4671005 external data monitoring committee for
their dedication and their diligent review of the data. We also
thank the following colleagues at Pfizer: Charlotte Allerton,
Mohanish Anand, Annaliesa Anderson, Jeremias Antinew,
Daniel Arenson, Edmund Arthur, Ayman Ayoub, Karen Baker,
Elizabeth Bateman, Arthur Bergman, Mary Boylon-Bost, Kevin
Brown, Carol Buck, Marjorie Buonanno, Paul Butler, Victoria
Butler, Regina Calderon, Anna Maria Calella, Rhonda Cardin,
Kristopher Chrisman, Ellen Chung Yi, Carol Connell, Tamara
Costopoulos, Darren Cowan, Donna Cox, Amit Dagar, Bernita Davies, Gabriela Davila, Caridad Del Castillo-Castaneda,
Gretchen Dean, Mikael Dolsten, Elizabeth Dushin, Martin Eck,
Susannah Fitzgerald, Michael T. Gaffney, Ramakanth GSH, Eileen Mary Girten, Marie-Pierre Hellio Le Graverand-Gastineau,
Jim Huang, Ileana Ionita, Farhad Kazazi, David Keller, Kelly
Kincaid, Charles Knirsch, Stephen Langman, Catherine Lee,
Joep Lelieveld, Cathy Q. Li, Katherine Liau, Carlos Linn, Marianne Lorenzen, Rod MacKenzie, Kannan Natarajan, Demetris
Neophytou Zambas, Seleen Ong, Russ Orrico, Dafydd Owen,
Seema Pai, Shyam Parvatini, Claire Penick, Jay Purdy, Amanda
Radola, Kathleen Reilly Thompson, Amy Robey, Liz Rodgers,
Glenda Rojas, Eve Rowe, Jean Satish, Cara Sclafani, Namita
Singh, Ravi Shankar Singh, Phylinda Chan, Kawleen Singh
Oberoi, Karen Singletary, Lisa Skeens, Patricia Smith, Holly
Soares, Karan Somasundar, Anna Spolnik, Craig Stevenson,
Kathleen Szymczak, Margaret Tawadrous, Manjit Toor, Arianna Trevisiol, Sarah Tweedy, Sophie Van De Leest, Jia Yi Liang,
and all the colleagues not named here who contributed to the
success of this trial. We thank Judith Kandel, Ph.D., Sheena
Hunt, Ph.D., and Tricia Newell, Ph.D. of ICON, who wrote the
first draft of the manuscript under direction from the authors,
with funding from Pfizer.
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11
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n e w e ng l a n d j o u r na l
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